Nerve growth factor (NGF) is a naturally occurring secreted protein which consists of an alpha, beta and gamma polypeptide chain. NGF is a member of the neurotrophin family and is implicated in a number of different roles. NGF promotes survival and differentiation of sensory and sympathetic neurons and signals via two membrane bound receptors, p75, a low affinity NGF receptor and TrkA, a transmembrane tyrosine kinase and a high affinity NGF receptor. The binding of NGF to TrkA or p75 results in an upregulation of neuropeptides in sensory neurons.
The use of NGF antagonists to treat pain and pain sensitivity in humans has been described (Cattaneo A., Curr. Op. Mol. Ther. 2010 12(1):94-106). For example, International Patent Application No. WO 2006/131951 describes a humanised form of the rat alphaD11 (αD11, αD11) monoclonal antibody. The αD11 antibody has binding specificity to mouse NGF, but is also known to bind to human and rat forms of NGF. Humanisation of the αD11 rat derived monoclonal antibody is required prior to administration to humans in order to minimise the production of neutralising antibodies which result from a human anti-mouse antibody (HAMA) response being mounted against rodent derived antibodies. Furthermore, the replacement of mouse constant domains with human constant domains allows downstream effector functions to be selected for.
Pain management in canines is currently provided through administration of analgesic drugs of several classes, including local and general anaesthetics, opioid analgesics, α2 agonists, non-steroidal anti-inflammatory drugs (NSAIDs) and steroids. Each of these needs to be administered frequently and also has limitations in efficacy and safety. There is accordingly a need for an infrequently dosed, long lasting and efficacious form of pain relief for canines suffering from chronic pain, such as those with cancer pain or arthritis.
While NGF is expressed in canine tissues and the canine NGF molecule has been characterised (Eisele I. Wood I S. German A J. Hunter L. Trayhurn P. “Adipokine gene expression in dog adipose tissues and dog white adipocytes differentiated in primary culture” Hormone & Metabolic Research. 37(8):474-81, 2005 Genbank XP_540250), no antagonist to canine NGF has been described, nor has the use of blocking NGF mediated signalling in canines to prevent or alleviate pain. The use in canines of known antibodies which act as anti-NGF antagonists in other species would not be feasible due to the production of neutralising antibodies. Furthermore, the production of a chimeric antibody comprising canine derived constant domains and variable domains derived from a known anti-NGF antibody such as alphaD11 could not be guaranteed to bind to canine NGF. Furthermore, such an antibody may exhibit cross-reactivity to other target epitopes which may be present in canines, but not present in the species from which the antibody was originally derived. Furthermore, the production of neutralising antibodies would limit the long term therapeutic administration of the antibody, this being a particularly important requirement when treating a chronic pain related condition or a cancerous condition. Likewise, the production of a caninised form of an anti-NGF antibody using CDR grafting, or a related technique may also result in neutralising antibody production and may further exhibit a reduction in antigen binding affinity and avidity. Accordingly, there is a serious need for binding members which act as antagonists of canine NGF for use in pain management in canines, wherein the binding members retain high levels of binding affinity and avidity, while avoiding the production of neutralising antibodies there against.